KR101766969B1 - Novel compound for the treatment of breast cancer and use thereof - Google Patents
Novel compound for the treatment of breast cancer and use thereof Download PDFInfo
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- KR101766969B1 KR101766969B1 KR1020150139934A KR20150139934A KR101766969B1 KR 101766969 B1 KR101766969 B1 KR 101766969B1 KR 1020150139934 A KR1020150139934 A KR 1020150139934A KR 20150139934 A KR20150139934 A KR 20150139934A KR 101766969 B1 KR101766969 B1 KR 101766969B1
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- South Korea
- Prior art keywords
- compound
- hydroxyphenyl
- breast cancer
- present
- dimethylamino
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- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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Abstract
The present invention, the novel histone diacetyl la kinase (HDAC) 3- (dimethylamino) as inhibitors - N 1 - hydroxy - N 8 - (2- hydroxyphenyl) octane-diamide compound or a pharmaceutically acceptable salt thereof As an active ingredient, to a pharmaceutical composition for preventing or treating breast cancer. According to the novel compounds of the present invention, since they act specifically on breast cancer without acting on normal cells or other types of cancer, it is possible to solve the side effect problems associated with conventional chemotherapeutic treatment of HDAC inhibitors.
Description
The present invention, the novel histone diacetyl la kinase (HDAC) 3- (dimethylamino) as inhibitors - N 1 - hydroxy - N 8 - (2- hydroxyphenyl) octane-diamide compound or a pharmaceutically acceptable salt thereof As an active ingredient, to a pharmaceutical composition for preventing or treating breast cancer.
The widespread genetic modification by histone or DNA modification, not DNA mutation, is known to be important for gene expression regulation. For example, histone deacetylase (HDAC, Histone deacetylase) inhibits histone acetylation and inhibits the expression of cell proliferation inhibitors, thereby promoting cell proliferation and controlling tumor cell differentiation and differentiation.
Therefore, HDAC has been attracting much attention as a target for treatment of various diseases including cancer and inflammatory diseases (Korean Patent No. 10-1543983), and histone deacetylase inhibitor (HDI) is a histone and non-histone protein The tumor suppressor gene selectively induces the expression of the tumor suppressor gene which is inhibited in its expression in a transcription-dependent / independent manner through acetylation-related mechanism. In fact, Vorinostat (suberoylanilide hydroxamic acid) (SAH), the first clinically approved HDI, has shown positive clinical results in a variety of solid cancer or blood cancer patients.
However, there have been a lot of side effects such as fatigue, diarrhea, and thrombocytopenia. Currently, existing candidate drug candidates that modify the structure of the compound by using the compound as a parent also selectively inhibit the target protein Has a low anticancer efficacy or toxicity even if its anticancer efficacy is high. In fact, most of the anticancer drugs used in clinical practice have a problem of killing not only cancer cells but also normal cells, which causes side effects such as vomiting, dizziness, anorexia and hair loss during chemotherapy.
Breast cancer is the most common malignant tumor that causes more than 40,000 deaths annually in women. Early diagnosis is crucial, but despite the many known chemotherapeutic agents, the survival rate is improved It is not possible. Chemotherapy, which is a typical chemotherapy, is used as the most effective treatment for treating cancer, alone or in combination with other therapies such as radiation therapy. However, the efficacy of a cancer treatment drug in chemotherapy is to kill cancer cells There is a problem in that it can act not only on cancer cells but also on ordinary cells when drugs are used.
Accordingly, the present inventors devised / synthesized a novel compound that specifically acts on breast cancer cells and is non-toxic to normal cells or other cancers, thereby completing the present invention.
Accordingly, it is an object of the present invention to provide a novel hydroxamate-based HDAC inhibitor compound, a method for synthesizing the same, and a pharmaceutical composition for preventing or treating breast cancer containing the compound as an active ingredient.
However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.
The present invention provides a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof and a process for producing the same.
[Chemical Formula 1]
The present invention also provides a pharmaceutical composition / health functional food for preventing, ameliorating or treating breast cancer, containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient.
The present invention also provides a method of preventing or treating breast cancer, comprising administering the compound or a pharmaceutically acceptable salt thereof to a subject.
In addition, the present invention provides the use of the compound or a pharmaceutically acceptable salt thereof for the prevention or treatment of breast cancer.
The present invention also provides a process for preparing said compound, comprising the steps of:
(a) reacting 2-aminophenol with epsilon -caprolactone in the presence of trimethylaluminum (AlMe 3 ) and tetrahydrofuran (THF) to prepare 6-hydroxy- N- (2-hydroxyphenyl) hexanamide ;
(b) oxidizing the 6-hydroxy- N - (2-hydroxyphenyl) hexanamide to produce N - (2-hydroxyphenyl) -6-oxohexanamide;
(c) Methyl 8- ((2-hydroxyphenyl) amino) -2-oxohexanoic acid was obtained from said N- (2-hydroxyphenyl) -8-oxo-oct-2-enoate;
(d) methyl 3- (dimethylamino) -8 (2-hydroxyphenyl) amino) -8-oxo-2-enoate was obtained from the methyl 8 - - ((2-hydroxyphenyl) amino) -8-oxo octanoate; And
(e) reacting the methyl 3- (dimethylamino) -8 - ((2-hydroxyphenyl) amino) -8-oxo octanoate with NH 2 OH.HCl in the presence of methanol and potassium hydroxide to give 3- dimethylamino) - N 1 - hydroxy - N 8 - (2- hydroxyphenyl) preparing an octane-diamide.
In one embodiment of the invention, the compound is characterized by being a histone deacetylase (HDAC) inhibitor.
In another embodiment of the invention, the compound is characterized by breast cancer specificity.
According to the novel compound of the present invention, it is possible to solve the side effect problems associated with the anticancer treatment of the existing HDAC inhibitors, and thus it is possible to provide a novel therapeutic agent specifically for breast cancer.
In addition, according to the method for synthesizing the novel compounds of the present invention, it is possible to eliminate the number of steps from the synthesis of various candidate substances to the target protein binding and cytotoxicity test, and to design the optimal molecular structure, As the effect can be confirmed, the synthesis efficiency can be greatly increased.
Accordingly, the present invention can provide an effective treatment method that specifically acts on breast cancer without acting on normal cells or other types of cancer using a newly synthesized HDAC inhibitor.
1 shows a structural formula of a borinostart (SAHA) compound approved as an anticancer agent in the prior art.
Fig. 2 is a schematic diagram for designing the breast cancer-specific anticancer agent of the present invention using a borinostart (SAHA) compound as a parent.
FIG. 3 is a spectrum analysis of the structure of the breast cancer-specific anticancer compound of the present invention (FIG. 3a: C 13 NMR, FIG. 3b: H 1 NMR, FIG. 3c: IR,
FIG. 4 shows the result of evaluating cytotoxicity by the WST-1 assay in order to confirm whether the compound of the present invention does not act on mammary gland cells but exclusively on breast cancer cells.
FIG. 5 is a result of evaluating cytotoxicity of WST-1 assay on other carcinomas (ovarian cancer, colon cancer) to confirm that the compound of the present invention is a breast cancer-specific anticancer agent that does not act on other carcinomas other than breast cancer.
The present inventors have found that a newly designed and synthesized histone deacetylase inhibitor exhibits toxicity only in breast cancer cells and non-toxic in normal cells and other cancer cells, and thus it can be effectively used for the development of breast cancer therapeutic agents.
In the present invention, in order to discover a novel histone deacetylase inhibitor, which is not previously known, using the borinostart (SAHA) compound shown in Fig. 1 as a parent, the selectivity is increased in the 14 Å carbon tunnel at the third carbon position in the SAHA crystal structure (-NH2), and an alcohol group (-OH) was added to the aromatic rings of SAHA to increase the water solubility while increasing the anticancer activity.
In the existing studies, since the carbon bridge portion of SAHA is surrounded by the oil-soluble tunnel, the oil-soluble substituents are mainly bonded at the third carbon position. However, in the present invention, focusing on selective binding rather than the affinity factor of the protein environment Candidate materials were devised. That is, it was pointed out that by arranging the nitrogen atom which is a polar molecule at the? -Position of the substituent, the metal bond (Zn 2 + ) with the catalytically active portion of the protein can be increased and the specificity of the effect can be increased (see FIG. 2) .
Thus, the reason for choosing the third carbon position of SAHA's carbon bridge to bind the nitrogen substituent is modeled by a previous study of a unique inhibitor that inhibits the overproduction of proteins associated with breast cancer. Although inhibitors that selectively inhibit specific proteins have been developed in the metal binding moiety and the capping group that are closely related to the catalytic activity of SAHA, In order to develop a specific chemotherapeutic agent for breast cancer, it is necessary to study the synthesis and effects of various molecules through the process of structure-activity relationship (SAR) by computer programming. It must go through the process.
At this time, the structure-activity relationship analysis (SAR) means that the biological activity of a drug such as antimicrobial activity, long-term affinity, and toxicity varies greatly depending on the type and number of substituents in the molecule as well as the precursor structure of the drug. And biological activity. One drug is induced to many derivatives and analogues by biochemical methods, but its physicochemical properties (eg pKa, Rf value, solubility, dipole moment, etc.) and its biological activity (MIC , LD, Km, etc.), it becomes possible to design and design a chemotherapeutic agent called selective toxicity.
Therefore, according to the present invention, in order to develop a specific anticancer agent showing the selection / concentration effect on a specific cell called breast cancer without affecting normal cells, unlike the conventional design method in the approach, Instead of omitting multiple screening steps to select efficacy and cytotoxicity tests after selecting the hit ligand, the optimal molecular structure can be designed at once by SAR analysis, and its efficacy and specificity can be measured only by cytotoxicity test Increased efficiency.
Further, in the present invention, the inventive compound was obtained by a novel synthesis method (see the schematic diagram of Example 2). First, the starting material is an easy-to-handle and relatively inexpensive ε-caprolactone compound (a), and the ring-opening is induced using Lewis acid (trimethyl aluminum, AlMe 3 ) (b). Then, the aldehyde compound (c) is obtained through a Swern oxidation process, and the length of the carbon linkage is extended by Horner-Wadsworth-Emmons reaction without further purification to obtain a compound (d) 3 was added to obtain a compound (e) having a nitrogen substituent bonded at the third carbon position. Finally, compound (e) was converted to a hydroxamate system under basic conditions to finally obtain a candidate breast cancer-specific anticancer drug (1).
Compounds designed and synthesized in this way show that SAHA (100 nM), known as a typical HDAC inhibitor (anticancer agent), is toxic in both breast normal cells (
In addition, SAHA (50 uM or more) showed cytotoxicity against ovarian cancer (SK-OV-3) and colorectal cancer (HCT-15) in addition to breast cancer while the compound of the present invention inhibited cancer cells other than breast cancer , Colon cancer) did not show cytotoxicity.
These results indicate that the compound of the present invention can be effectively used as an anticancer agent specific to breast cancer only without affecting normal cells or other carcinomas, thereby solving the problem of side effects of conventional anticancer agents.
The pharmaceutical composition of the present invention represented by the following general formula (1), 3- (dimethylamino) - N 1 - hydroxy - N 8 - (2- hydroxyphenyl) octane-diamide, compound or a pharmaceutically acceptable salt thereof As an active ingredient.
[Chemical Formula 1]
As the 'pharmaceutically acceptable salt' in the present invention, an acid addition salt formed by a free acid is useful. The acid addition salt is prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution, and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be subjected to suction filtration.
In the present invention, the term " treatment or prevention of breast cancer " is meant to include alleviation of breast cancer, alleviation of symptoms and improvement of symptoms, and lowering the likelihood of breast cancer.
The compositions of the present invention may further comprise components such as conventional therapeutically active ingredients, other adjuvants, pharmaceutically acceptable carriers, and the like. Herein, the pharmaceutically acceptable carrier includes those conventionally used in the formulation, including saline, sterilized water, Ringer's solution, buffered saline, cyclodextrin, dextrose solution, maltodextrin solution, glycerol, ethanol, liposome and the like And may further include other conventional additives such as an antioxidant, a buffer and the like as needed. It may also be formulated into injectable formulations, pills, capsules, granules or tablets, such as aqueous solutions, suspensions, emulsions and the like, with the addition of diluents, dispersants, surfactants, binders and lubricants. Suitable pharmaceutically acceptable carriers and formulations can be suitably formulated according to the respective ingredients using the method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA. The pharmaceutical composition of the present invention is not particularly limited to a formulation, but may be formulated into injections, inhalants, external skin preparations, and the like.
In the present invention, the term 'individual' refers to a subject in need of treatment for diseases, and more specifically refers to a human or non-human primate, mouse, rat, dog, cat, It means mammals.
The term "pharmaceutically effective amount" as used herein refers to the type and severity of the disease to be treated, the age and sex of the patient, the sensitivity to the drug, the administration time, the administration route and the release rate, Can be readily determined by those skilled in the art in an amount that is determined by factors well known in the medical arts, and can be maximized without adverse effects, taking into account all of the above factors. The daily dose refers to the amount of the therapeutic substance of the present invention which is sufficient to treat a relieved disease state by being administered to an individual in need of treatment. As a non-limiting example, the dosage for the human body of the composition according to the present invention may vary depending on the age, weight, sex, dosage form, health condition and disease severity of the patient and is based on adult patients weighing 70 kg , It is generally 0.01 to 1000 mg / day, preferably 1 to 500 mg / day, and may be dividedly administered once to several times a day at predetermined time intervals.
The method of administering the pharmaceutical composition of the present invention is not particularly limited, but it may be parenterally or orally administered intravenously, subcutaneously, intraperitoneally, by inhalation, skin application or topical application according to the intended method.
When the composition of the present invention is prepared with a food composition, it may contain ingredients that are conventionally added in the manufacture of foods in addition to the active ingredient, and may include, for example, proteins, carbohydrates, fats, nutrients, flavoring agents, and flavoring agents . For example, when the food composition of the present invention is prepared as a drink, citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, fruit juice and the like may be further included.
Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.
[ Example ]
Example 1: Design of candidate breast cancer-specific anticancer drugs
The breast cancer-specific anticancer drug candidate was designed by structure-activity correlation analysis (SAR) using the borinostart (SAHA) compound shown in Fig. 1 as a parent.
That is, in order to discover a novel histone deacetylase inhibitor, which is not known in the prior art, a substituent (-NH2) capable of increasing the selectivity to a 14-angstrom space tunnel at the third carbon position in the SAHA crystal structure is added, The addition of an alcohol group (-OH) to SAHA 's directional ring enhances its anticancer activity and water solubility. By arranging the nitrogen atom, which is a polar molecule, at the α-position of the substituent, the metal bond (Zn 2+ ) with the catalytically active portion of the protein can be increased to increase the specificity of the effect.
Example 2: Synthesis of candidates for breast cancer-specific anticancer drugs
Based on the results designed in Example 1, a candidate compound (1) for breast cancer-specific anticancer drug was synthesized, and a specific synthesis procedure is shown in the following schematic diagram. The starting materials, reagents and solvents used in the following synthesis were purchased from Sigma, Daejeong Reagent Co., Ltd., and used. The water-sensitive reactions were carried out in a vessel dried with argon gas and the vessel used for iron-sensitive reaction was washed with a mixed solvent of hydrochloric acid and distilled water (1: 1) and dried. The silica gel used in the column chromatography was also washed with a mixed solvent of hydrochloric acid and distilled water (1: 1) and washed with methanol three times or more.
[Synthesis diagram of compound (1)] [
2-1. Compound (b): 6-hydroxy- N - (2-hydroxyphenyl) hexanamide Synthesis
To a solution of compound (a) ε-caprolactone (0.56 mL, 5.0 mmol, 114.14 g / mol) in THF (50 mL) at 0 ° C. under argon gas was added trimethyl aluminum (3.75 mL, 7.5 mmol, 2M in toluene) 2-aminophenol (0.68 mL, 7.5 mmol, 109.13 g / mol) was added stepwise. After stirring for 3 hours at room temperature, 1.0 M hydrochloric acid was added and stirred until the gas bubbles disappeared. Diethyl ether (20 mL) was added to the mixture and the mixture was washed three times with water (10 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to give the residue, 6-hydroxy- N- (2-hydroxyphenyl) hexanamide, which was purified by column chromatography (10% acetone / CH 2 Cl 2 ) 42%). 1 H-NMR (δ, ppm , CHLOROFORM-D): 1.52 (m, 2H), 1.59 (m, 4H), 2.51 (m, 2H), 3.70 (m, 2H), 4.70 (bs, 1H), 7.00 (t, IH), 7.04 (t, 2H), 7.14 (d, IH), 8.90 (bs, IH).
2-2. Compound (c): N - (2-hydroxyphenyl) -6-oxohexanamide Synthesis
To a solution of DMSO (78.13 g / mol, 1.1 g / mL, 0.91 mL, 12.74 mmol, 3.3 eq.) In CH 2 Cl 2 (38.6 mL, 0.1 M) under argon gas at-78 ° C was added oxalyl chloride (126.93 g / mol (B) 6-Hydroxy- N- (2-hydroxyphenyl) hexanamide (854 mg, 3.86 mmol) was added stepwise after slowly adding 1.48 g / mL, 0.50 mL, 5.79 mmol, 1.5 eq. Triethylamine (TEA, 101.19 g / mol, 0.7255 g / mL, 3.66 mL, 26.25 mmol, 6.8 eq.) Was slowly added to the reaction mixture at -78 ° C for 45 minutes and further stirred at room temperature for 1 hour. Water (38.6 mL) was then added, diluted with CH 2 Cl 2 (12.7 mL) and then washed with 10% hydrochloric acid (12.7 mL), saturated aqueous NaHCO 3 (51.3 mL) and brine (51.3 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to give the residue, N - (2-hydroxyphenyl) -6-oxohexanamide, which was used in the next step without purification.
2-3. Compound (d): methyl 8 - ((2- hydroxyphenyl ) amino) -8- oxooct -2- enoate synthesis
To a solution of NaH (24.00 g / mol, 157 mg, 6.56 mmol, 1.7 eq.) In THF (38.6 mL, 0.1 M) was added trimethylphosphonoacetate (182.11 g / mol, 1.26 g / 6.56 mmol, 1.7 eq.) Was added slowly and stirred for 15 min. The compound (c) N - (2-hydroxyphenyl) -6-oxohexanamide (221.26 g / mol, 3.86 mmol) was added to the reaction mixture and stirred for 15 minutes and further stirred at room temperature for 1 hour. After addition of saturated aqueous NH 4 Cl, the mixture was stirred until the gas bubbles disappeared and washed three times with water (38.6 mL) and diethyl ether (38.6 mL). The organic layer was dried over Na 2 SO 4 , filtered and evaporated to give methyl 8 - ((2-hydroxyphenyl) amino) -8-oxooct-2-enoate as a residue and purified by column chromatography (diethyl ether: petroleum ether 3: 2) (985 mg, 92%). (E + Z) -isomers 1 H -NMR (δ, ppm, CHLOROFORM-D): 1.54 (m, 2H), 1.76 (m, 2H), 2.38 (t, 2H), 2.68 (q, 2H), 3.71 (s, 3H), 5.82 (d, IH), 5.79 (d, IH), 6.24 (m, IH, J = 180 Hz), 6.94 (t, 1 H), 7.51 (d, 1 H), 8.90 (bs, 2H).
2-4. Compound (e): methyl 3- (dimethylamino) -8 - ((2-hydroxyphenyl) amino) -8-oxooctanoate
At room temperature under argon gas, CH 3 CN (38.6mL, 20M ) of 1,8-diazabicyclo [5.4.0] undec- 7-ene (DBU, 152.24 g / mol, 1.018 g / mL, 0.11 mL, 0.76mmol, 1eq (D) methyl 8 - ((2-hydroxypheny) amino) -8-oxooct-2-enoate (277.32 g / mol, 210 mg, 0.76 mmol) 0.67 g / mL, 0.1 mL, 1.52 mmol, 2 eq.) Was added stepwise. After stirring for 6 hours, the residue was concentrated without further purification to obtain methyl 3- (dimethylamino) -8- (2-hydroxyphenyl) amino-8-oxooctanoate as a residue. The residue was purified by column chromatography (Ethyl acetate: Hexane 1: 10% Acetone / DCM), (10% MeOH / DCM) (210 mg, 86%).
2-5. The final compound (1): 3- (dimethylamino) - N One -hydroxy- N 8 - (2-hyroxyphenyl) octanediamide Synthesis
To a solution of NH 2 OH.HCl (69.49 g / mol, 452 mg, 6.5 mmol, 10 eq.) In methanol (6.5 mL, 0.1 M) at 0 ° C was added KOH (56.11 g / mol, 729 mg, eq.) was slowly added and stirred for 20 minutes. (E) methyl 3- (dimethylamino) -8- (2-hydroxyphenyl) amino) -8-oxooctanoate (322.41 g / mol, 210 mg, 0.65 mmol) 6.0). Washed with water then dilute with ethyl acetate (30 mL), the organic layer is Na 2 SO 4 to a dried, filtered and evaporated to give 3- (dimethylamino) the remainder is water the final compound - N 1 -hydroxy- N 8 - ( 2- hyroxyphenyl) octanediamide was obtained and purified by column chromatography (8% MeOH / CH 2 Cl 2 ) (98 mg, 47%). 1 H-NMR (δ, ppm , METHANOL-D4): 1.30 (m, 2H), 1.44 (m, 1H), 1.61 (m, 3H), 2.47 (t, 2H), 2.60 (s, 7H), 2.82 (m, 1H), 3.33 (m, 1H, J = 180 Hz), 7.09 (t, 2H), 7.29 (t, 1H), 7.63 (d, 1H); 13 C-NMR (?, Ppm, METHANOL-D4): 26.8, 30.4, 34.5, 37.2, 40.7, 52.8, 63.6, 117.4, 120.8, 124.1, 127.0, 127.2, 149.9, 173.7, 174.9; IR: 3674, 3308, 2927, 2859, 1713, 1651, 1598, 1524, 1496, 1417, 1362, 1309, 1281, 1221, 1085, 1005, 959, 752, 684 cm -1 ; HRMS (EI-TOF, m / z ): found [M] 323.1846, calc. for C 16 H 25 N 3 O 4 , 323.1845.
Example 3: Structural analysis of candidate breast cancer-specific anticancer drugs
The molecular structure and purity of the candidate substance synthesized in Example 2 were analyzed by H 1 NMR, C 13 NMR, IR (Infrared Spectroscopy) and HRMS (High Resolution Mass Spectrometer) analysis.
At this time, the NMR spectra were measured with Bruker AVANCE III 700 and Varian Unity 300 spectrometer. Deuterium chloroform or deuterated methanol was used as the solvent. IR spectrum was measured by
Showed in a to d in FIG. 3 the spectrum results, analysis to confirm that the structural formula of '3- (dimethylamino) - N 1 - hydroxy - - N 8 (2- hydroxyphenyl) octane-diamide, compound Respectively. 1 H-NMR (δ, ppm , METHANOL-D4): 1.30 (m, 2H), 1.44 (m, 1H), 1.61 (m, 3H), 2.47 (t, 2H), 2.60 (s, 7H), 2.82 (m, 1H), 3.33 (m, 1H, J = 180 Hz), 7.09 (t, 2H), 7.29 (t, 1H), 7.63 (d, 1H); 13 C-NMR (?, Ppm, METHANOL-D4): 26.8, 30.4, 34.5, 37.2, 40.7, 52.8, 63.6, 117.4, 120.8, 124.1, 127.0, 127.2, 149.9, 173.7, 174.9; IR: 3674, 3308, 2927, 2859, 1713, 1651, 1598, 1524, 1496, 1417, 1362, 1309, 1281, 1221, 1085, 1005, 959, 752, 684 cm -1 ; HRMS (EI-TOF, m / z ): found [M] 323.1846, calc. for C 16 H 25 N 3 O 4 , 323.1845.
Example 4: Evaluation of breast cancer specific cytotoxicity
The cytotoxicity of the candidate compound identified in Example 3 was evaluated using a WST-1 assay (Roche) in order to confirm whether the candidate compound specifically reacted with breast cancer cells without reacting with normal cells or other carcinomas.
The WST-1 cytotoxicity assay to quantify cell viability is to measure the production of formazan by ELISA in the tetrazolium salts (WST-1) produced by intracellular mitochondrial dehydrogenase. This is due to the dehydrogenase present in the mitochondrial electron transport system of metabolically active cells. It is effective only for living cells, and the intensity of color is linear with the number of cells.
First, normal cells were seeded at 8 × 10 3 cells / well in 96 well plates, and cancer cells (breast cancer, ovarian cancer, colon cancer) were seeded at a concentration of 5 × 10 3 cells / well. The compound, SAHA (control group), was treated with cells at concentrations of 100 pM, 50 nM, 100 nM, 50 uM and 100 uM, respectively. After incubation for 24, 48, and 72 hours at 5% CO 2 and 37 ° C, the absorbance at 440 nm was measured using a VERSA max microplate reader (Molecular Devices) .
As a result, as shown in FIG. 4, in the case of treatment with SAHA (100 nM), cytotoxicity was observed in both breast normal cells (MCF-10A) and breast cancer cells (MCF7-bus) inhibitor, 100 nM) did not show cytotoxicity on normal mammary cells but only on breast cancer cells.
As shown in FIG. 5, when SAHA (50 uM or more) was treated, cytotoxicity was shown to ovarian cancer (SK-OV-3) and colorectal cancer (HCT-15) in addition to breast cancer, The compound (selective inhibitor) was not cytotoxic to other cancer cells other than breast cancer.
Therefore, the compound of the present invention is excellent as an anticancer agent specific for breast cancer. Therefore, the compound of the present invention does not affect normal cells, thereby solving the problem of side effects of conventional anticancer agents (SAHA).
Claims (6)
[Chemical Formula 1]
(a) reacting 2-aminophenol with epsilon -caprolactone in the presence of trimethylaluminum (AlMe 3 ) and tetrahydrofuran (THF) to prepare 6-hydroxy- N- (2-hydroxyphenyl) hexanamide ;
(b) oxidizing the 6-hydroxy- N - (2-hydroxyphenyl) hexanamide to produce N - (2-hydroxyphenyl) -6-oxohexanamide;
(c) Methyl 8- ((2-hydroxyphenyl) amino) -2-oxohexanoic acid was obtained from said N- (2-hydroxyphenyl) -8-oxo-oct-2-enoate;
(d) methyl 3- (dimethylamino) -8 (2-hydroxyphenyl) amino) -8-oxo-2-enoate was obtained from the methyl 8 - - ((2-hydroxyphenyl) amino) -8-oxo octanoate; And
(e) reacting the methyl 3- (dimethylamino) -8 - ((2-hydroxyphenyl) amino) -8-oxo octanoate with NH 2 OH.HCl in the presence of methanol and potassium hydroxide to give 3- dimethylamino) - N 1 - hydroxy - N 8 - (2- hydroxyphenyl) preparing an octane-diamide.
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